tbuckley/cabot-search huggingface dataset:
Aristolochic acid (AA) exposure and telomere maintenance mechanism in liver angiosarcoma (AS).
Authors: Tom Wei-Wu Chen, Chia-Lang Hsu, Yu-Ching Wu, Da-Liang Ou, Yung-Yeh Su, Ann-Lii Cheng, Chiun Hsu
Journal: Journal of Clinical Oncology (2023)

11551 Background: Liver AS has a grave prognosis and our previous study (Chen TW et al. Cancer 2022) showed that the incidence of liver AS is higher in Asia. We aimed to investigate the etiology of liver AS and its molecular characteristics. Methods: We performed whole exome (WES) and transcriptome sequencing (RNA-seq) of AS (liver 10, scalp 5, breast 2, trunk 1, heart 1) and hepatocellular carcinoma (HCC, 9) from National Taiwan University Hospital (NTUH) and re-analyzed WES &amp; RNA-seq of AS from the Count Me In Project (CMI, 46). Somatic mutations and copy number alternation were called by Mutect2 and Sequenza from tumor-normal matched WES. Non-negative matrix factorization was used to determine mutational signature profiles and the contributions of each signature to each sample. Telomere length was estimated using TelSeq. Results: We identified four single-base-substitution (SBS) signatures using somatic mutations from 74 (AS/HCC 65/9) WES data. The dominated signature in liver AS had exceptionally high cosine similarity (93.08%) with COSMIC SBS22 (ver 3.2), which is related to AA exposure. The AA-mutation signature contributed significantly (adjusted p &lt; 0.01) to the DNA mutations in 70% (7/10), 0% (0/9), 7% (3/46), and 56% (5/9) of liver AS (NTUH), nonliver AS (NTUH), CMI AS, and HCC (NTUH), respectively. TP53 (60% vs 22% vs 32%) and ATRX (40% vs 0% vs 11%) mutations were more common in liver than nonliver AS (NTUH) or CMI, while KDR mutation rates were similar (30% vs 44% vs 22%). Among TP53 mutations from liver AS with AA signature, 86% (6/7) showed the typical A:T &gt; T:A mutation caused explicitly by AA-induced DNA damage. In liver vs nonliver AS, the median number of mutations and neoantigen burdens were 6.55 vs 0.98 (p = 0.0076) and 1572 vs 544 (p = 0.095), respectively. Although liver AS and HCC were highly associated with AA-mutation signature, liver AS had significantly longer telomeres in terms of tumor/normal telomere ratio (median 1.27 vs 1.16, p = 0.0009) but a significantly lower telomerase enzyme activity (p = 0.016). We did not find an association between ATRX mutation, or its mRNA expression level, with the extended telomere length in liver AS. Compared to nonliver AS, the activity of the telomere replication molecule BUB1 was significantly higher in liver AS (p = 0.0029). Conclusions: Our study is the first to connect AA exposure to the etiology of liver AS. The high mutation rate and distinct telomere maintenance mechanism of liver AS provides insights into future treatments.
Efficacy and safety of dose-escalated alectinib in patients with metastatic ALK-positive NSCLC and CNS relapse on standard dose alectinib.
Authors: Justin Matthew Cheung, Jiyoon Kang, Beow Y. Yeap, Jenn Peterson, Andrew Do, Subba R Digumarthy, Justin F. Gainor, Jessica Jiyeong Lin
Journal: Journal of Clinical Oncology (2023)

e21079 Background: Central nervous system (CNS) metastases represent a common cause of morbidity and mortality in patients (pts) with ALK-positive (ALK+) non-small cell lung cancer (NSCLC), with limited therapeutic options. We previously reported re-induction of CNS responses using dose intensification of alectinib in two pts with metastatic ALK+ NSCLC who had experienced CNS progression on standard dose alectinib. However, this strategy has not been assessed in larger cohorts. Methods: In this retrospective study, pts were eligible if they had advanced ALK+ NSCLC with CNS relapse on standard dose alectinib (600 mg twice daily) and subsequently received dose-escalated alectinib (900 mg twice daily). Medical records and radiographic imaging were reviewed to determine treatment outcomes. CNS efficacy was assessed per the modified Response Evaluation Criteria in Solid Tumors version 1.1. Treatment-related adverse events (trAEs) were graded per the CTCAE version 5.0. Results: 27 pts were eligible [male, 67%; median age at diagnosis, 53 (range, 31-69)]. Pts had previously received median 3 lines of systemic therapy (range, 1-12) and median 2 ALK TKIs (range, 1-4); all had received standard dose alectinib with CNS progression. 19 pts (70%) had received prior CNS-directed radiotherapy (RT) [median time from most recent RT to dose-escalated alectinib, 13.9 months (mos) (range, 0.2-52.3)]. The median duration of dose-escalated alectinib therapy in this cohort was 7.7 mos (95% CI, 4.8-10.9), with median overall progression-free survival (PFS) of 7.8 mos (95% CI, 4.9-13.7). Among 25 response-evaluable pts with baseline measurable or non-measurable CNS metastases, the CNS objective response rate (ORR) was 8.0% (95% CI, 1.0-26.0), with 2 pts having intracranial complete responses. CNS disease control rate (DCR) was 92.0% (95% CI, 74.0-99.0), with median CNS duration of response (DoR) of 5.3 mos (95% CI, 3.4-8.3) and median CNS PFS of 7.1 mos (95% CI, 4.4-13.7). Of 3 patients with baseline measurable CNS disease, all 3 had best intracranial response of SD, and median CNS PFS was 6.7 mos (95% CI, 6.2-not reached). Dose-escalated alectinib was well tolerated with no drug discontinuation due to trAE and no grade 3 or higher trAEs. One pt required dose reduction to 750 mg twice daily due to intolerable grade 2 fatigue. 23 pts (85%) experienced grade 1-2 trAEs. Grade 1-2 trAEs that occurred in 10% of pts were anemia (52%), fatigue (37%), constipation (26%), bilirubin increase (15%), alkaline phosphatase increase (15%), and peripheral neuropathy (11%). Conclusions: Dose intensification of alectinib demonstrated meaningful efficacy and tolerability in pts with metastatic ALK+ NSCLC who had experienced CNS disease relapse on standard dose alectinib, and may represent a viable therapeutic option for re-establishing CNS disease control.
Demographic and clinical factors associated with cardiovascular events in elderly long-term survivors of breast cancer.
Authors: Sarah Westvold, Madhav KC, Jane Fan, Terry Hyslop, Lisa Spees, Shi-Yi Wang, Andrea Silber, Kevin C. Oeffinger, Michaela Ann Dinan
Journal: Journal of Clinical Oncology (2023)

e24105 Background: Improvements in cancer-specific survival have led to a growing appreciation for non-cancer drivers of mortality, particularly cardiovascular disease (CVD), in long-term cancer survivors. However, studies of population-level, non-oncologic outcomes in long-term survivors as a function of treatment exposures remain limited. Our aim is to evaluate the risk of developing cardiovascular disease (CVD) based on demographic and clinical characteristics in long-term breast cancer survivors, defined as those alive five years after diagnosis. Methods: We conducted a SEER-Medicare retrospective study of patients over age 65 with non-metastatic breast cancer, treated with curative intent surgery, diagnosed between 2003-2011, and enrolled in fee-for-service Medicare. CVD events were defined by the presence of any claims corresponding to stroke, heart failure, myocardial infarction, or cardiomyopathy beginning at 5 years after initial diagnosis and extending through year 10. Chi-squared tests were used to examine associations between demographic and clinical characteristics and CVD status. LASSO regularization was used for variable selection in a cox-proportional hazards model using 10-fold cross validation showing CVD hazard ratios stratified by diagnosis year. Results: 43,347 patients met inclusion criteria, of which 5,444 had a diagnosis of CVD between five years after diagnosis and last follow-up. Compared to patients without evidence of CVD, patients experiencing CVD were more likely to be older, Black, live in impoverished neighborhoods, have stage III (vs. I or II) disease, and have been diagnosed during the latter part of the study period (2009-2011 vs. 2003-2008). Variables included in the model following the LASSO regularization process were age at diagnosis, race/ethnicity, % with poverty, metropolitan residence, cancer stage at diagnosis, receipt of radiation therapy, and diagnosis year. Age, race/ethnicity, and cancer stage at diagnosis were significant predictors of developing CVD during years 5-10 after an initial cancer diagnosis (P &lt; 0.001). Risk of developing CVD increased with age and was associated with a threefold higher risk in women over age 85. Non-Hispanic Black patients were at the highest risk across race/ethnicity groups (HR: 1.48, 95% CI: 1.34 – 1.65), and patients with a stage III diagnosis were at the highest risk by stage (ref Stage I; HR: 1.56, 95% CI: 1.41 - 1.72). Those diagnosed in 2009-2011 were at higher risk of developing CVD than in earlier years (ref 2003-2005; HR: 1.67, 95% CI: 1.56 – 1.79). Conclusions: Age, race, poverty, and cancer stage at diagnosis were associated with increased risk of developing CVD in long-term breast cancer survivors. Patients with elevated non-oncologic risks may benefit from increased participation by primary care as a component of effective cancer survivorship.
Temozolomide plus cisplatin versus toripalimab (anti-PD-1) as adjuvant therapy in resected mucosal melanoma.
Authors: Bin Lian, Hui Tian, Lu Si, Zhihong Chi, Xinan Sheng, Xuan Wang, Lili Mao, Xue Bai, Bixia Tang, Xieqiao Yan, Siming Li, Li Zhou, Xiaoting Wei, Juan Li, Caili Li, Chuanliang Cui, Jun Guo
Journal: Journal of Clinical Oncology (2023)

9508 Background: Chemotherapy (temozolomide plus cisplatin) has been demonstrated to be a better adjuvant regimen compared to high-dose interferon alpha-2b in resected Mucosal Melanoma (MuM) in the pre-immunotherapy era. Yet in the present immunotherapy era, PD-1 inhibitor was recommended as a standard adjuvant therapy for resected Melanoma. No adjuvant trial comparing chemotherapy with PD-1 inhibitor in resected MuM had been reported. we conducted this study to determine the efficacies of adjuvant chemotherapy versus PD-1 inhibitor in resected MuM. Methods: All patients (pts) with resected MuM received chemotherapy (temozolomide 200 mg/m 2 /day orally on days 1 to 5 plus cisplatin 75 mg/m 2 i.v. on days 1-3, repeated every 3 weeks for six cycles) or Toripalimab (anti-PD-1, 3 mg/kg every 2 weeks via intravenous infusion) as adjuvant therapy from 2013 to 2019 were included retrospectively. Demographic and clinical characteristics between the two groups were matched with 1:1 by propensity score matching (PSM) to reduce the bias. After PSM, the efficacies of the two groups were compared, and subgroup analysis was performed according to the baseline characteristics. The endpoints were relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). Kaplan-Meier methods and Cox regressions were used to estimate median RFS, DMFS, OS and HR. Results: A total of 247 pts were included, of which 78 were in the Toripalimab group and 169 were in the Chemo group. PSM matched 65 pts from each of the two groups. The baseline characteristics were similar. At a median follow-up of 52.6 months (95%CI, 44.6-60.6 months), patients receiving chemo had a longer median RFS (28.2 vs. 12.0 months; HR=0.64, 95% CI, 0.42 to 0.98; P=0.04), DMFS (42.0 vs. 19.0 months; HR=0.58, 95% CI, 0.36 to 0.92; P=0.02) and OS (93.4 vs. 39.3 months; HR=0.56, 95% CI, 0.33 to 0.94; P=0.03) versus the toripalimab group (Table). Conclusions: Adjuvant chemotherapy (temozolomide plus cisplatin) shows remarkable longer RFS, DMFS, and OS than Toripalimab (anti-PD-1). It suggested that adjuvant chemotherapy may be a better option for patients with resected mucosal melanoma even in the present immunotherapy era. [Table: see text]
Anthracycline-related cardiotoxicity among patients with lymphoma: Systematic review and meta-analysis.
Authors: Anan Abdelmoti Abu Rmilah, Vidur Kailash, Naba Farooqui, Sae Jang, Kathryn Jean Ruddy, Saro Armenian, Daniel John Lenihan, Charles L. Loprinzi, Joerg Herrmann
Journal: Journal of Clinical Oncology (2023)

e19517 Background: Anthracycline-induced cardiotoxicity (AIC) is a well-known phenomenon, but event rates and predictors may not be as robust as commonly perceived. We performed a systematic review and meta-analysis to elucidate AIC definitions, incidence rates and predictors. Methods: 5323 reports were identified via searching Medline, Embase, and Scopus. Inclusion criteria for full text review included minimum of 100 lymphoma patients receiving ACs; median/mean follow up of at least 12 months; and specified evaluation of left ventricular ejection fraction. We investigated the definition, reported incidence, and predictors of AIC including subclinical AIC as detected by decrease in left ventricular systolic dysfunction. Meta-analysis was performed with Meta-analyst software with random effects model. Results: A total of 19 studies were included in the analysis. The overall incidence of AIC in 13926 patients was 13.8% (95% CI 4.8-22.8, I 2 99.6% p &lt; 0.001) at a mean/median follow-up ranging from 1 to 8 years. Subclinical AIC was seen in 8.2% of 5464 patients (95% CI 6.4 to 10%, I 2 78.9%, p &lt; 0.001) at a mean/median follow-up ranging from 1 to 20 years. Subclinical AIC is defined in most studies as asymptomatic decrease in LVEF by 10-15% from baseline of 50-55%. Older age, increasing AC dose or number of cycles, GLS (global longitudinal strain), and prior comorbidities such as CAD, HTN, DM and dyslipidemia were found to predict AIC. However, Heterogeneity was seen in definition of AIC, risk factor assessment and follow-up protocol, which limited the extent of correlative analyses for cardiotoxicity predictors. Conclusions: The overall incidence of clinical HF and subclinical AIC among lymphoma patients was 13.8% and 8.2% respectively. Older age, increasing AC dose or number of cycles, GLS, and prior comorbidities such as CAD, HTN, DM and dyslipidemia were found to predict AIC.
Amplification of wild-type <i>RET</i> and clinical response to selpercatinib for non–small-cell lung cancer (NSCLC).
Authors: Malini Marion Gandhi, Biagio Ricciuti, Melissa Gildenberg, Ankit Singh, Yvonne Y. Li, Andréanne Gagné, Xinan Wang, Kelly Fitzgerald, Ayal Aizer, Mizuki Nishino, Joao Victor Machado Alessi, Federica Pecci, Alessandro Di Federico, Adam Fisch, Valentina Nardi, Lynette M. Sholl, Mark M. Awad, Julia K. Rotow
Journal: Journal of Clinical Oncology (2023)

9123 Background: RET rearrangements and RET kinase domain mutations represent targetable genomic alterations in various cancer types. However, the frequency and characteristics of RET amplification in cancer and its potential role as a targetable oncogenic driver are not well-characterized. Methods: In a pan-cancer cohort of patients at the Dana-Farber Cancer Institute (DFCI) whose tumors underwent next-generation sequencing (NGS), we evaluated the frequency of wild-type (wt) RET amplification (defined as ≥6 copies) in the absence of RET rearrangements or activating mutations. We validated our findings using merged data from the TCGA, GENIE, and China Pan-Cancer datasets. Results: The frequency of wt RET amplification across all cancers was 0.08% (28/34,463) in the DFCI cohort and 0.16% (145/91,466) in the validation cohort. In NSCLC, the frequency of RET amplification was 0.10% (5/4773) in the DFCI cohort and 0.13% (15/11,622) in the validation cohort. Other cancer types with RET amplification included hepatobiliary cancer, prostate cancer, and breast cancer, among others. For 22 RET-amplified cases with available copy number data , the median RET gene copy number was 7 (range 6-36). Among 20 RET-amplified NSCLCs, 10 had no other known driver mutations, and 10 had concurrent driver mutations (including MET exon 14 skipping, MET amplification, KRAS G12C/S/D, EGFR L858R, EGFR exon 20 insertion, and EGFR exon 19 deletion). In cases with available smoking status, 5 out of 6 patients with RET-amplified NSCLC had a history of tobacco use. A 69-year-old man with unresectable stage III NSCLC had disease recurrence after chemoradiation and durvalumab. Both the initial and recurrent biopsy samples showed focal high-level RET amplification (22 and 28 copies, respectively); genomic and RNA sequencing showed no other driver mutations or RET rearrangements. He experienced partial response to the selective RET inhibitor selpercatinib with decrease of both intracranial and systemic tumor burden. Conclusions: Amplification of wt RET represents a novel, targetable, rare molecular subset of NSCLC and other cancers.
Real-world evidence to inform clinical insights on tissue-agnostic approvals of therapies.
Authors: George W. Sledge, Takayuki Yoshino, Joanne Xiu, Anthony Helmstetter, Sergey Klimov, Brady Gilg, Matthew James Oberley, Milan Radovich, Jim Abraham, David Spetzler
Journal: Journal of Clinical Oncology (2023)

6589 Background: Many tissue-agnostic (TA) approvals were based on clinical trials with limited patient numbers without covering all tissue types (TT), raising the question of whether these indications were truly tissue agnostic. Real world evidence (RWE) offers an opportunity to investigate TTs not included in clinical trials/studies to answer this question. Herein we investigate the seven TA approvals to date in a large real world database and report clinical outcomes. Methods: A total of 186,581 tumors from over 35 TTs tested with comprehensive molecular profiling including NextGen sequencing of DNA and RNA were investigated for TA alterations (TMB-High (≥10 mutations/MB), MSI-H/MMRd, BRAF V600E mutations and NTRK1/2/3/RET fusions) at Caris Life Sciences (Phoenix, AZ). Time-on-treatment (TOT) from RWE was obtained from insurance claims and calculated from treatment start to finish. Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Significance was determined as p values of &lt;0.05. Results: Among all tumors, 21.2% carried at least one TA alteration, 17.2%, 3.4% and 0.6% had 1, 2 or 3 alterations, respectively. TMB-H in 18.7%, MSI-H/dMMR was seen in 3.9%, BRAF V600E in 2.8% of tumors, NTRK1/2/3 and RET fusion seen in 0.16% and 0.23%. TA alterations were most prevalent in BCC (86%) &amp; SCC (82%) of skin, MEL (71%), THCA (51%) and NSCLC (44%) and least in liposarcoma (0), meningioma (0.7%) and GIST (1.4%). Among tumors treated based on TA indications, substantial variability of TOT among TTs was observed (see table). Looking at TTs included (INC) and not included (nINC) in KEYNOTE-158 and other studies for TMB-H and pembro, median TOT for nINC was similar to INC (N=242 vs 2322, 6.1 m vs 6.3 m, p = 0.55). Nevertheless, statistically significant differences in median TOTs were seen across nINC when comparing TMB-H vs. TMB-L (6.1m vs. 2.9m, HR: 0.58 [95% CI: 0.50-0.67], p&lt;0.001) and in a subset of 838 MSS tumors (4.9m vs. 2.8m, p&lt;0.001). Conclusions: RWE data adds substantially to our understanding of the demographics of TA indications and suggests that some TA treatment benefits may be tissue-specific. Recent TA indications will require further accumulation of cases to draw meaningful conclusions regarding whether TA indications are, in fact, tissue agnostic. [Table: see text]
Tislelizumab plus chemotherapy in patients with advanced brain metastases of non-squamous non-small cell lung cancer: A multicenter, prospective, open-label phase 2 study.
Authors: Yan Huang, Qitao Yu, Nong Yang, Li Liu, Yan Yu, Qiming Wang, Yuanyuan Zhao, Yunpeng Yang, Wei Jiang, Liping Tan, Chunhua Zhou, Fanxu Zeng, Kai Zhang, You Qin, Shuai Zhang, Shuxiang Ma, Li Zhang
Journal: Journal of Clinical Oncology (2023)

9080 Background: Patients (pts) with brain metastases (BM) were usually unrepresented in clinical trials assessing the efficacy of PD-(L) 1 inhibitors. Here, we investigated the efficacy and safety of tislelizumab (TIS) plus chemotherapy in NSCLC pts with asymptomatic untreated BM or with stable BM after local radiotherapy. Methods: This multicenter, prospective, open-label phase 2 study enrolled systemic treatment-naïve pts with stage IV non-squamous (nsq) NSCLC without EGFR or ALK mutations who had BM. Pts received TIS combined with pemetrexed and carboplatin for 4 cycles, followed by maintenance TIS and pemetrexed. RECIST v1.1 and RANO-BM were applied for assessment for systematic and brain disease, respectively. The primary endpoint was the investigator-assessed 1-year PFS rate per RECIST v1.1. Results: 36 pts were enrolled with 77.8% having stage IVB disease, 25.0% liver metastases and 41.7% bone metastases. 29 (80.6%) pts were with untreated, asymptomatic brain metastases, and the other 7 (19.4%) received radiotherapy for BM previously. As of 30 Nov 2022, the median follow-up was 12.3 months. 1-year systematic PFS rate was 36.8% (95% CI, 18.0-55.7), with median PFS of 7.5 months (95% CI, 5.1-NE). Systematic ORR was 50.0% (95% CI, 31.9-68.1%). Median OS was not reached, with 1-year OS rate of 70.5% (95% CI, 51.7-83.1). For intracranial efficacy assessment per RANO-BM, 1-year intracranial PFS (iPFS) rate was 56.6 % (95% CI, 31.7-75.5), with 45.5% (95% CI, 19.4, 68.5) and 100% in pts with untreated and pretreated BM, respectively. Intracranial ORR was 56.7% (95% CI, 37.4-74.5%), with 53.8% (95% CI, 33.4-73.4%) in pts with untreated BM and 75% (95% CI, 19.4-99.4%) in pretreated BM. No grade 5 toxicities were observed. Grade 3-4 TRAEs occurred in 33.3% (12/36) of pts. 13.9% of pts experienced irAEs; grade 3-4 irAEs occurred in 2 (5.6%) pts. Conclusions: TIS plus chemotherapy yielded promising systematic and intracranial PFS, and was generally well tolerated in nsq-NSCLC pts with untreated or pretreated BM. Clinical trial information: NCT04507217 . [Table: see text]